WO2020163150A1 - Valvules cardiaques régénératrices renforcées - Google Patents

Valvules cardiaques régénératrices renforcées Download PDF

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Publication number
WO2020163150A1
WO2020163150A1 PCT/US2020/015892 US2020015892W WO2020163150A1 WO 2020163150 A1 WO2020163150 A1 WO 2020163150A1 US 2020015892 W US2020015892 W US 2020015892W WO 2020163150 A1 WO2020163150 A1 WO 2020163150A1
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WIPO (PCT)
Prior art keywords
tissue
regenerative
heart valve
derived
cells
Prior art date
Application number
PCT/US2020/015892
Other languages
English (en)
Inventor
Ankita BORDOLOI GURUNATH
Hao Shang
Jingjia HAN
Original Assignee
Edwards Lifesciences Corporation
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Edwards Lifesciences Corporation filed Critical Edwards Lifesciences Corporation
Priority to EP20708898.0A priority Critical patent/EP3920848A1/fr
Priority to CN202080021587.8A priority patent/CN113573668A/zh
Priority to CA3127232A priority patent/CA3127232A1/fr
Publication of WO2020163150A1 publication Critical patent/WO2020163150A1/fr
Priority to US17/393,624 priority patent/US20210361421A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61F—FILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, e.g. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
    • A61F2/00—Filters implantable into blood vessels; Prostheses, i.e. artificial substitutes or replacements for parts of the body; Appliances for connecting them with the body; Devices providing patency to, or preventing collapsing of, tubular structures of the body, e.g. stents
    • A61F2/02—Prostheses implantable into the body
    • A61F2/24—Heart valves ; Vascular valves, e.g. venous valves; Heart implants, e.g. passive devices for improving the function of the native valve or the heart muscle; Transmyocardial revascularisation [TMR] devices; Valves implantable in the body
    • A61F2/2412—Heart valves ; Vascular valves, e.g. venous valves; Heart implants, e.g. passive devices for improving the function of the native valve or the heart muscle; Transmyocardial revascularisation [TMR] devices; Valves implantable in the body with soft flexible valve members, e.g. tissue valves shaped like natural valves
    • A61F2/2418—Scaffolds therefor, e.g. support stents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61F2/00—Filters implantable into blood vessels; Prostheses, i.e. artificial substitutes or replacements for parts of the body; Appliances for connecting them with the body; Devices providing patency to, or preventing collapsing of, tubular structures of the body, e.g. stents
    • A61F2/02—Prostheses implantable into the body
    • A61F2/24—Heart valves ; Vascular valves, e.g. venous valves; Heart implants, e.g. passive devices for improving the function of the native valve or the heart muscle; Transmyocardial revascularisation [TMR] devices; Valves implantable in the body
    • A61F2/2412—Heart valves ; Vascular valves, e.g. venous valves; Heart implants, e.g. passive devices for improving the function of the native valve or the heart muscle; Transmyocardial revascularisation [TMR] devices; Valves implantable in the body with soft flexible valve members, e.g. tissue valves shaped like natural valves
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
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    • A61L27/38—Materials for grafts or prostheses or for coating grafts or prostheses containing ingredients of undetermined constitution or reaction products thereof, e.g. transplant tissue, natural bone, extracellular matrix containing added animal cells
    • A61L27/3804—Materials for grafts or prostheses or for coating grafts or prostheses containing ingredients of undetermined constitution or reaction products thereof, e.g. transplant tissue, natural bone, extracellular matrix containing added animal cells characterised by specific cells or progenitors thereof, e.g. fibroblasts, connective tissue cells, kidney cells
    • A61L27/3834—Cells able to produce different cell types, e.g. hematopoietic stem cells, mesenchymal stem cells, marrow stromal cells, embryonic stem cells
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    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/50—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
    • A61L27/507—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials for artificial blood vessels
    • A—HUMAN NECESSITIES
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    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/50—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
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    • A—HUMAN NECESSITIES
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    • A61F—FILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, e.g. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
    • A61F2220/00—Fixations or connections for prostheses classified in groups A61F2/00 - A61F2/26 or A61F2/82 or A61F9/00 or A61F11/00 or subgroups thereof
    • A61F2220/0025—Connections or couplings between prosthetic parts, e.g. between modular parts; Connecting elements
    • A61F2220/005—Connections or couplings between prosthetic parts, e.g. between modular parts; Connecting elements using adhesives
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    • A61F2220/00—Fixations or connections for prostheses classified in groups A61F2/00 - A61F2/26 or A61F2/82 or A61F9/00 or A61F11/00 or subgroups thereof
    • A61F2220/0025—Connections or couplings between prosthetic parts, e.g. between modular parts; Connecting elements
    • A61F2220/0075—Connections or couplings between prosthetic parts, e.g. between modular parts; Connecting elements sutured, ligatured or stitched, retained or tied with a rope, string, thread, wire or cable
    • A—HUMAN NECESSITIES
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    • A61F—FILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, e.g. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
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    • A61F2250/0067—Means for introducing or releasing pharmaceutical products into the body
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    • A61F2250/0058—Additional features; Implant or prostheses properties not otherwise provided for
    • A61F2250/0082—Additional features; Implant or prostheses properties not otherwise provided for specially designed for children, e.g. having means for adjusting to their growth
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    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
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    • A61L2430/00—Materials or treatment for tissue regeneration
    • A61L2430/20—Materials or treatment for tissue regeneration for reconstruction of the heart, e.g. heart valves

Definitions

  • the application is generally directed to regenerative heart valves, and more specifically to reinforced regenerative heart valves for heart valve replacement.
  • Valvular stenosis and regurgitation are a few of number of complications that may necessitate a heart valve replacement.
  • Traditional replacement valves are constructed from various biocompatible metals, polymers and animal pericardium tissue. These valvular prostheses often have known limitations, including lifetime use of blood thinners, valve lifetime expectancy of 10 to 20 years, and/or inability to
  • a heart valve capable of growing and integrating within the site of replacement is desired.
  • Regenerative tissue heart valves are an intriguing solution to overcome the limitations of traditional replacement valves.
  • Regenerative tissue heart valves are bioengineered valves produced in vitro. Because regenerative valves are live growing tissue, the valves have plasticity and remodeling capability that may allow them to integrate and grow at a site of replacement. Based on these qualities, regenerative tissue valves are a highly desirable option for procedures requiring valve replacement.
  • Many embodiments are directed to devices and methods to reinforce regenerative heart valves.
  • an implantable device for heart valve replacement includes a regenerative heart valve comprising regenerative tissue and a first ring structure adapted to be situated at the base of the heart valve to provide support for the regenerative tissue such that when the heart valve is situated at the site of replacement, the regenerative tissue can grow and integrate with native tissue while maintaining the valvular shape of the heart valve.
  • an implantable device for heart valve replacement further includes a first tissue layer encasing the first ring structure such that the first tissue layer mitigates the first ring structure from being exposed to the native surrounding tissue when situated at the site of replacement.
  • the heart valve is an aortic valve and the first ring structure provides sufficient support such that the regenerative tissue is able to grow in presence of forces that occur in the native aortic root.
  • the first ring structure is further adapted to expand as the heart valve annulus expands.
  • the first ring structure is segmented into at least one segment having two overlapping ends that allow expansion.
  • the two overlapping ends are fastened together using a pin on a first end and a receptive guide on a second end.
  • the pin has a pinhead extending orthogonally from the first end and the guide has a hollowed portion configured to fit the pinhead, and wherein the guide further has a an aperture to allow the pin to move in one direction such that the two ends move in opposing directions.
  • the first ring structure is an overlapping coiled ring.
  • the first ring structure is a compressed garter spring.
  • the first ring structure is constructed from a biodegradable material.
  • the biodegradable material is selected from the group consisting of: polyglycolic acid (PGA), polylactic acid (PLA), poly- Ddactide (PDLA), polyurethane (PU), poly-4-hydroxybutyrate (P4HB), and
  • PCL polycap rolactone
  • the biodegradable material is designed to degrade approximately in a timeframe selected from: 6, 12, 18, 24, 30 and 36 months.
  • the first tissue layer is adapted to capture degraded particles of the first ring structure.
  • the first ring structure is constructed from a metallic material.
  • the metallic material is selected from the group consisting of: stainless steel, cobalt-chromium alloys, titanium, and titanium alloys.
  • the first ring structure is attached to the base of the heart valve, and wherein the attachment is provided by sutures or an adhesive.
  • a second ring structure adapted to be situated on the effluent side of the heart valve to provide support for the regenerative tissue such that when the heart valve is situated at the site of replacement, the regenerative tissue can grow and integrate with native tissue while maintaining the valvular shape of the heart valve and a second tissue layer encasing the second ring structure, wherein the second tissue layer mitigates the first ring structure from being exposed to the native surrounding tissue when situated at the site of replacement.
  • the second ring is expandable.
  • the tissue sleeve is formed from pericardial tissue derived from an animal source.
  • the tissue sleeve is formed from autologous tissue derived from an individual to be treated.
  • the tissue of the regenerative heart valve is formed in vitro.
  • the tissue of the regenerative heart valve is formed from autologous tissue derived from an individual to be treated.
  • the tissue of the regenerative heart valve is grown a biodegradable scaffold.
  • the biodegradable scaffold is made of material selected from a group consisting of: collagen, chitosan, decellularized extracellular matrix, alginate, and fibrin.
  • the regenerative heart valve is trained in a bioreactor system that simulates physiological and mechanical pressures that occur in the aortic root.
  • the tissue of the regenerative heart valve is grown from a cell source selected from the group consisting of: mesenchymal stem cells, cardiac progenitor cells, endothelial progenitor cells, adipose tissue, vascular tissues, amniotic fluid-derived cells, and cells differentiated from pluripotent stem cells.
  • the cell source is mesenchymal stem cells derived from human bone marrow.
  • the cell source is vascular tissue derived from peripheral arteries or umbilical veins.
  • the tissue of the regenerative heart valve incorporates bioactive molecules.
  • biomolecules promote the production of
  • the biomolecules are selected from the group consisting of: vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF), transforming growth factor-b (TGF-6), angiopoietin 1 (ANGPT1), angiopoietin 2 (ANGPT2), insulin-like growth factor 1 (IGF-1) and stromal-derived factor- 1-a (SDF-l-a).
  • VEGF vascular endothelial growth factor
  • bFGF basic fibroblast growth factor
  • TGF-6 transforming growth factor-b
  • ANGPT1 angiopoietin 1
  • ANGPT2 angiopoietin 2
  • IGF-1 insulin-like growth factor 1
  • SDF-l-a stromal-derived factor- 1-a
  • biomolecules mitigate
  • an implantable device for supporting tissue regeneration at a heart valve includes a regenerative heart valve comprising regenerative animal tissue and a tubular wall adapted to be situated to surround the effluent side of the regenerative heart valve when implanted into an individual, the tubular is further adapted to provide rigid support for the regenerative heart valve such that when situated on the effluent side of the heart valve the regenerative tissue can grow and integrate with native tissue while maintaining the valvular shape of the heart valve.
  • the heart valve is an aortic valve and the tubular wall provides sufficient support such that the regenerative tissue is able to grow in presence of forces that occur in the native aortic root.
  • the internal face of the tubular wall is engineered to promote regeneration of the regenerative heart valve and the native surrounding tissue.
  • the internal face of the tubular wall has a contour pattern that includes a set of ridges or furrows that are spaced such that regenerative cells are able to align and pattern to assist in formation of an endothelium dike tissue layer.
  • the set of ridges or furrows are offset at a distance that is greater than the average size of a cell associated with pannus formation.
  • the internal face is coated or impregnated with bioactive molecules.
  • bioactive molecules promote vascular regeneration and differentiation.
  • bioactive molecules attracts native endothelial progenitors.
  • the bioactive molecules are selected from the group consisting of: vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF), transforming growth factor-b (TGF-6), angiopoietin 1 (ANGPT1), angiopoietin 2 (ANGPT2), insulin-like growth factor 1 (IGF-1) and stromal-derived factor- 1-a (SDF-l-a).
  • VEGF vascular endothelial growth factor
  • bFGF basic fibroblast growth factor
  • TGF-6 transforming growth factor-b
  • ANGPT1 angiopoietin 1
  • ANGPT2 angiopoietin 2
  • IGF-1 insulin-like growth factor 1
  • SDF-l-a stromal-derived factor- 1-a
  • biomolecules mitigate
  • biological cells are integrated within or coated onto the internal face.
  • the cells are derived from an autologous source.
  • the cells are derived from a source selected from: mesenchymal stem cells, cardiac progenitor cells, endothelial progenitor cells, adipose tissue, vascular tissues, amniotic fluid-derived cells, and cells
  • the cell source is mesenchymal stem cells derived from human bone marrow.
  • the cell source is vascular tissue derived from peripheral arteries or umbilical veins.
  • the tubular wall is attached the regenerative heart valve, and wherein the attachment is provided by sutures or an adhesive.
  • the tubular is constructed from a biodegradable material.
  • the biodegradable material is selected from the group consisting of: polyglycolic acid (PGA), polylactic acid (PLA), poly- Ddactide (PDLA), polyurethane (PU), poly-4-hydroxybutyrate (P4HB), and
  • PCL polycap rolactone
  • the biodegradable material is designed to degrade approximately in a timeframe selected from: 6, 12, 18, 24, 30 and 36 months.
  • the tissue of the regenerative heart valve is formed in vitro.
  • the tissue of the regenerative heart valve is formed from autologous tissue derived from an individual to be treated.
  • the tissue of the regenerative heart valve is grown a biodegradable scaffold.
  • the biodegradable scaffold is made of material selected from the group consisting of: collagen, chitosan, decelhdarized extracellular matrix, alginate, and fibrin.
  • the regenerative heart valve is trained in a bioreactor system that simulates physiological and mechanical pressures that occur in the aortic root.
  • the tissue of the regenerative heart valve is grown from a cell source selected from the group consisting of: mesenchymal stem cells, cardiac progenitor cells, endothelial progenitor cells, adipose tissue, vascular tissues, amniotic fluid-derived cells, and cells differentiated from pluripotent stem cells.
  • a cell source selected from the group consisting of: mesenchymal stem cells, cardiac progenitor cells, endothelial progenitor cells, adipose tissue, vascular tissues, amniotic fluid-derived cells, and cells differentiated from pluripotent stem cells.
  • the cell source is mesenchymal stem cells derived from human bone marrow.
  • the cell source is vascular tissue derived from peripheral arteries or umbilical veins.
  • the tissue of the regenerative heart valve incorporates bioactive molecules.
  • biomolecules promote the production of
  • the biomolecules are selected from the group consisting of: vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF), transforming growth factor-b (TGF-6), angiopoietin 1 (ANGPT1), angiopoietin 2 (ANGPT2), insulin-like growth factor 1 (IGF-1) and stromal-derived factor- 1-a (SDF-l-a).
  • VEGF vascular endothelial growth factor
  • bFGF basic fibroblast growth factor
  • TGF-6 transforming growth factor-b
  • ANGPT1 angiopoietin 1
  • ANGPT2 angiopoietin 2
  • IGF-1 insulin-like growth factor 1
  • SDF-l-a stromal-derived factor- 1-a
  • biomolecules mitigate
  • FIG. 1A provides a perspective view illustration of an embodiment of regenerative heart valve with a support ring.
  • Fig. IB provides an elevation view illustration of an embodiment of regenerative heart valve with a support ring.
  • FIG. 2A provides an elevation view illustration of an embodiment of regenerative heart valve with a support ring and tissue sleeve.
  • FIG. 2B provides a cross-sectional view illustration of an embodiment of regenerative heart valve with a support ring and tissue sleeve.
  • Fig. 3 provides a perspective view illustration of an embodiment of regenerative heart valve with multiple support rings.
  • Fig. 4 provides a top view illustration of an embodiment of a segmented ring.
  • Fig. 5 provides an elevation view illustration of an embodiment of a joint between two ends of a segmented ring.
  • Fig. 6A provides an exploded perspective view illustration of an embodiment of a joint between two ends fastened using a pin and guide for use with a segmented ring.
  • Fig. 6B provides a top view illustration of an embodiment of an end having a guide for use with a segmented ring.
  • FIG. 7 provides a top view illustration of an embodiment of a coiled ring.
  • Fig. 8 provides a top view illustration of an embodiment of a garter spring ring.
  • FIG. 9A provides a perspective view illustration of an embodiment of a regenerative heart valve with a surrounding support wall.
  • FIG. 9B provides a cut-out perspective view illustration of an embodiment of a regenerative heart valve with a surrounding support wall.
  • a reinforcing element in accordance with several embodiments, provides structure and rigidity to withstand stresses that occur in the aortic root, where the forces related to systole and diastole pressures are strong and repetitive.
  • a reinforcing element prevents and/or mitigates a regenerative heart valve from collapsing.
  • a reinforcing element helps a regenerative heart valve maintain shape within the aortic root after implantation.
  • a reinforcing element is biodegradable.
  • a number of synthetic biodegradable polymers can be used, in accordance with various embodiments
  • a support ring including (but not limited to) polyglycolic acid (PGA), polylactic acid (PLA), poly-D-lactide (PDLA), polyurethane (PU), poly-4- hydroxybutyrate (P4HB), and polycaprolactone (PCL).
  • PGA polyglycolic acid
  • PLA polylactic acid
  • PDLA poly-D-lactide
  • PU polyurethane
  • P4HB poly-4- hydroxybutyrate
  • PCL polycaprolactone
  • a reinforcing element that is constructed of a biocompatible metal or metal alloy, including (but not limited to) stainless steel, cobalt-chromium alloys, titanium, and titanium alloys.
  • a support ring is attached to the base of a
  • a support ring is encased within a tissue sleeve, providing a barrier between the ring and native tissue when implanted.
  • a support ring is expandable.
  • a tubular wall is provided surrounding a regenerative heart valve such that the wall provides structural support.
  • a surrounding wall promotes regeneration of a heart valve and/or the native luminal walls within the aortic root.
  • a support ring in accordance with several embodiments, provides structure and rigidity to withstand stresses that occur within an aortic root, where the forces related to systole and diastole pressures are strong and repetitive.
  • a support ring prevents and/or mitigates a regenerative heart valve from collapsing.
  • a support ring helps a regenerative heart valve maintain shape within the aortic root after implantation.
  • FIG. 1A is a perspective view and in Fig IB is an elevation view of an embodiment of a regenerative heart valve (101) having an attached ring (103) for reinforcement.
  • the heart valve (101) and attached ring (103) are to be utilized as heart valve replacement to treat heart valve disease.
  • Numerous embodiments are directed to regenerative heart valves to replace dysfunctional aortic valves, however, it should be understood that the mitral valve, tricuspid valve, and pulmonary valve can also be replaced. Blood flow through the heart valve is depicted by arrow 105.
  • the embodiment of the regenerative heart valve (101) has three leaflets (107a, 107b, and 107c) that are regenerative tissue.
  • the leaflets are joined and/or abut at the base (109) and the side commissures (111).
  • two or three leaflets are formulated in a regenerative heart valve, but it should be understood that number of leaflets can vary and still fall within some embodiments of the disclosure.
  • a replacement valve (101) When replacing an aortic valve, in accordance with various embodiments, a replacement valve (101) should be situated within the aortic root such that the base (109) and attached ring (103) are located at the aortic annulus, the top of the leaflets are located at the sinotubular junction, and blood flow follows arrow 105 ( e.g ., from left ventricle into ascending aorta).
  • a number of embodiments utilize regenerative tissue to form tissue portions of a regenerative heart valve, including leaflets.
  • a regenerative heart valve is grown in vitro prior to implantation in accordance with methods as understood in the art.
  • Regenerative Heart Valves see the description described within the section labeled“Regenerative Heart Valves,” which is provided herein.
  • a regenerative heart valve is to be inserted into an aortic root to replace a dysfunctional aortic valve, where the forces related to systole and diastole pressures are strong and repetitive.
  • regenerative heart valves are generally composed of soft tissue and are highly plastic, they often lack sufficient rigidity to withstand strong pulsatile pressures.
  • an implanted regenerative heart valve can collapse, causing great damage and preventing the valve from properly integrating within an aortic root. Further growth and regeneration within an aortic root can also be inhibited as host cells will not have the ability to migrate and assimilate within a regenerative valve.
  • a reinforcing support ring that provides structural rigidity capable of withstanding constricting and pulsatile forces associated with blood pressure in the aortic root.
  • a reinforcing support ring maintains a regenerative heart valve’s shape and functionality while under stress from the blood pressure forces.
  • a biocompatible support ring (103) is attached to the base of a regenerative heart valve (101) at the base on the in-flow side.
  • a support ring provides rigidity and support to a regenerative heart valve.
  • a support ring is able to support a regenerative heart valve to withstand the forces within an aortic root such that the heart valve can maintain a valvular shape and continue regenerative growth post implantation. Accordingly, in some embodiments, a support ring has enough
  • a support ring has enough fatigue strength such that a regenerative heart valve is able to withstand pulsatile pressures associated with systole and diastole.
  • pressures within aortic root can be approximately 120 systolic mmHg in a typical human, and can reach above 150 systolic mmHg or even 180 systolic mmHg in an individual suffering from severe hypertension.
  • a regenerative heart valve is able to withstand pressures of at least 100 mmHg, 110 mmHg, 120 mmHg, 130 mmHg, 140 mmHg, 150 mmHg, 160 mmHg, 170 mmHg, or 180 mmHg.
  • a support ring is biodegradable.
  • a number of synthetic biodegradable polymers can be used, in accordance with various embodiments, to construct a support ring, including (but not limited to) polyglycolic acid (PGA), polylactic acid (PLA), poly-D-lactide (PDLA), polyurethane (PU), poly-4-hydroxybutyrate (P4HB), and polycaprolactone (PCL). It should be understood that multiple materials can be combined to construct a support ring.
  • a support ring is degraded after implantation over a period of time, which may allow host cells to migrate into and proximate to a regenerative valve such that the host cells can support the valve after the ring is degraded.
  • the ring will no longer be needed when the regenerative valve converts into host living tissue and adapts to the local environment, including withstanding forces within the aortic root.
  • a biodegradable support ring will degrade in a timeframe of 6 to 36 months.
  • biodegradable support ring will degrade in approximately 6, 12, 18, 24, 30 or 36 months. It should be understood that the material selected and thickness of a biodegradable support ring can be selected such that the time frame to degrade can be manipulated.
  • a support ring that is constructed of a biocompatible metal or metal alloy, including (but not limited to) stainless steel, cobalt-chromium alloys, titanium, and titanium alloys.
  • a metal or metal alloy support ring is durable will not corrode over time such that a host will not have issues with the ring.
  • a surface treatment and/or coating is performed on a metal or alloy support ring to resist corrosion.
  • a metal or alloy ring is adapted to be removed at some point after implantation.
  • a support ring is secured to the base of a regenerative heart valve on the in-flow side.
  • a support ring is secured to the base of a regenerative heart valve using sutures.
  • sutures used to secure a support ring to the base of a regenerative heart valve are bio- absorbable.
  • a support ring is secured to the base of a regenerative heart valve using a biocompatible adhesive.
  • a tissue sleeve encases a support ring to isolate the support ring from a host’s tissue at the site of implantation.
  • Figs. 2A and 2B are an elevation view and cross-section view of an embodiment of a regenerative heart valve (201) with a support ring (203) attached.
  • a tissue sleeve (205) Encasing the support ring (203) is a tissue sleeve (205).
  • any appropriate support ring constructed of any appropriate material is encased by a tissue sleeve in accordance of a number embodiments. Accordingly, in some embodiments, a tissue sleeve encases a metal or metal alloy ring. And in some embodiments, a tissue sleeve encases a biodegradable polymer.
  • a tissue sleeve completely surrounds and encases a support ring, which may provide a number of benefits.
  • the tissue sleeve protects the host from direct contact with the support ring post implantation.
  • tissue sleeve when a biodegradable polymer support ring is encased by a tissue sleeve, the tissue sleeve captures degraded fragments of the support ring, preventing degraded fragments from entering into a host’s circulatory system.
  • a tissue sleeve encasing can be derived from any appropriate tissue source.
  • regenerative tissue is utilized to form a tissue sleeve, which can integrate with a host’s native tissue post implantation.
  • the same regenerative tissue used to form a regenerative heart valve is used to form a tissue sleeve.
  • a tissue sleeve is formed from pericardial tissue derived from an animal source (e.g ., bovine, porcine).
  • a tissue sleeve in accordance with various embodiments, is grown in vitro in the presence of a support ring such that the tissue sleeve grows around the support ring to encase it.
  • a tissue sleeve is layered around a support ring and sutured to encase the support ring.
  • a support ring encased in a tissue sleeve is secured to the base of a regenerative heart valve on the in-flow side.
  • a support ring is encased in a tissue sleeve secured to the base of a regenerative heart valve using sutures.
  • sutures used to secure a support ring encased in a tissue sleeve to the base of a regenerative heart valve are bio- absorbable.
  • a support ring encased in a tissue sleeve is secured to the base of a regenerative heart valve using a biocompatible adhesive.
  • Various embodiments are also directed towards multiple support rings to provide support to a regenerative heart valve.
  • a regenerative heart valve (301) having two support rings (303a and 303b).
  • a second support ring is provided along the commissures of a regenerative heart valve to further support the valve.
  • further support is provided between multiple support rings in the form of a struts or a wire mesh.
  • a number of embodiments are directed to methods of delivering a support ring and/or regenerative valve to the site of deployment.
  • a method can be performed on any suitable recipient, including (but not limited to) humans, other mammals (e.g., porcine), cadavers, or anthropomorphic phantoms, as would be understood in the art.
  • methods of delivery include both methods of treatment (e.g., treatment of human subjects) and methods of training and/or practice (e.g., utilizing an
  • Methods of delivery include (but not limited to) open heart surgery and transcatheter delivery.
  • a catheter containing a support ring and/or regenerative valve is delivered via a guidewire to the site of deployment.
  • a support ring and/or regenerative valve is released from the catheter and then expanded into form such that the support ring is at the base of a regenerative heart valve.
  • expansion mechanisms can be utilized, such as (for example) an inflatable balloon, mechanical expansion, or utilization of a self-expanding device.
  • Particular shape designs and radiopaque regions on the frame and/or on the cover can be utilized to monitor the expansion and implementation.
  • a support ring and/or regenerative valve may be utilized in a variety of applications.
  • a support ring and/or regenerative device is delivered to a site for valve replacement, especially replacement of an aortic valve.
  • a number of embodiments are directed to support rings that are expandable.
  • a support ring as described herein, is a ring that supports a regenerative valve from the stresses that occur within the aortic root. It is desirable in some situations that a support ring be expandable as the aortic root expands. In many embodiments, a support ring provides outward radial forces to all the ring to expand as the aortic root expands. This is especially true in heart valve replacement procedures in growing children. Accordingly, in several embodiments a support ring is expandable such that the support can expand as the regenerative valve and/or native aortic root expands.
  • Fig. 4 Provided in Fig. 4 is an embodiment of a segmented support ring (401) that is expandable. As shown, the segmented support ring (401) has three segments (403a,
  • a segmented support ring can have any appropriate number of segments and joints, but minimally must have at least 1 segment having and one joint. In various embodiments, a segmented support ring has 1, 2, 3, 4, or 5 segment(s) and joint(s).
  • segments of a segmented support ring overlap at a joint.
  • Fig. 5 is an elevated view an embodiment of a joint (501) of a segmented support ring in which a first end of a segment (503) and a second end of a segment (505) overlap.
  • ends (503 and 505) could be ends of a single segment or ends of two separate segments.
  • overlapping segments of a segmented ring utilize a pin and guide to fasten a joint between two segment ends, but still allow expansion.
  • Fig. 6A is an exploded view of an embodiment of a joint (601) having a first end (603) and second end (605) that utilizes a pin (607) and guide (609). Note that the guide (609) is hollowed within the first end (603).
  • Fig. 6B is a top-down view of the first end (603) that has a guide (609) to accept the pin (607) of the second end.
  • the pin (607) has a head (611) wider than the aperture (613) of the guide (609) to secure the ends (603 and 605) together, yet still allow the ends to move in opposite directions as depicted by the arrow (615). Expansion of the joint (601) allows the segmented ring to expand.
  • a pin and guide are to be designed to such that the pin head fits within the hollowed portion of the guide but large enough that the pin head cannot pass through the aperture of the guide. Accordingly, in some embodiments, the width of the pin head is be wider than the width aperture while the width of the hollowed portion of the guide is wider than width of the pin head. Furthermore, in some embodiments, a connecting arm of the pin is to fit within the aperture of the guide such that the connecting arm can freely move in in at least one direction to allow expansion.
  • a pin head can be any appropriate shape, including (but not limited to) spherical, cylindrical, and cubical.
  • FIG. 7 is an embodiment of an overlapping coiled ring having outwardly radial forces.
  • Fig. 8 is an embodiment of a compression garter spring having outwardly radial forces.
  • an expandable support ring is biodegradable.
  • a number of synthetic biodegradable polymers can be used, in accordance with various embodiments, to construct a support ring, including (but not limited to) polyglycolic acid (PGA), polylactic acid (PLA), poly-Ddactide (PDLA), polyurethane (PU), poly-4- hydroxybutyrate (P4HB), and polycaprolactone (PCL). It should be understood that multiple materials can be combined to construct an expandable support ring.
  • an expandable support ring is degraded after implantation over a period of time, which may allow host cells to migrate into and proximate to a regenerative valve such that the host cells can support the valve after the ring is degraded.
  • the ring will no longer be needed when the regenerative valve converts into host living tissue and adapts to the local environment, including withstanding forces within the aortic root.
  • a biodegradable and expandable support ring will degrade in a timeframe of 6 to 36 months.
  • a biodegradable and expandable support ring will degrade in approximate 6, 12, 18, 24, 30 or 36 months. It should be understood that the material selected and thickness of a biodegradable and expandable support ring can be selected such that the time frame to degrade can be manipulated.
  • an expandable support ring that is constructed of a biocompatible metal or metal alloy, including (but not limited to) stainless steel, cobalt-chromium alloys, titanium, and titanium alloys.
  • a metal or metal alloy expandable support ring is utilized, it is expected that the metal ring will remain in a regenerative valve and integrate into the host after implantation.
  • a metal or alloy expandable support ring is durable will not corrode over time such that a host will not have issues with the ring.
  • a surface treatment and/or coating is performed on a metal or alloy expandable support ring to resist corrosion.
  • a metal or alloy ring is adapted to be removed at some point after implantation.
  • an expandable ring is secured to the base of a regenerative heart valve on the in-flow side to provide structural support.
  • an expandable support ring is secured to the base of a regenerative heart valve using sutures.
  • sutures used to secure an expandable ring to the base of a regenerative heart valve are bio- absorb able.
  • an expandable support ring is secured to the base of a regenerative heart valve using a biocompatible adhesive.
  • an expandable support ring is attached to a base of regenerative valve to provide structural support.
  • a tissue sleeve completely surrounds and encases an expandable support ring, which may provide a number of benefits.
  • the tissue sleeve protects the host from direct contact with the support ring post implantation.
  • the tissue sleeve captures degraded fragments of the support ring, preventing degraded fragments from entering into a host’s circulatory system.
  • a surrounding wall provides structural rigidity such that it provides structural support to a regenerative heart valve so that it can withstand stresses that occur within the aortic root.
  • a surrounding wall promotes regeneration of a regenerative heart valve by supplying regenerative factors that can promote host cells to migrate and convert within an implanted valve.
  • FIG. 9A Provided in Fig. 9A is a perspective view and provided in in Fig. 9B is a perspective view with a cut-out window of an embodiment of a regenerative heart valve (901) having a surrounding wall (903).
  • the surrounding wall (903) extends from the base area (905) of the valve to near the top or beyond the top of the leaflets (907).
  • a regenerative heart valve with surrounding wall is to be inserted into an aortic root to replace a dysfunctional aortic valve.
  • An outer face (909) of the supporting wall (903) is designed such that it contours to the native luminal surface in the aortic root.
  • An inner face (911) of the supporting wall can be etched to form furrows and/or coated with molecules to promote cellular integration within and regeneration of the heart valve (901).
  • a surrounding support wall provides structural support to regenerative valves within the aortic root, where the forces related to systole and diastole pressures are extremely strong and repetitive. Because regenerative heart valves are generally composed of soft tissue and are highly plastic, they lack sufficient rigidity to withstand strong pulsatile pressures. Thus, a newly implanted regenerative heart valve can be forced to collapse, causing great damage and preventing the valve from properly integrating the aortic root. Further growth and regeneration within the aortic root can also be inhibited as host cells will not have the ability to migrate and assimilate within the regenerative valve.
  • a reinforcing wall that provides structural rigidity capable of withstanding the constricting and pulsatile forces associated with blood pressure in the aortic root.
  • a reinforcing wall maintains a regenerative heart valve’s shape and functionality while under stress from the blood pressure forces.
  • a surrounding wall is attached to a regenerative heart valve. In some embodiments, a surrounding wall is attached at the base of a
  • a surrounding wall is unattached to a regenerative heart valve but remains within proximity to the valve when implanted such that it is surrounding the valve.
  • a surrounding wall provides rigidity and support to a regenerative heart valve.
  • a surrounding wall is able to support a regenerative heart valve to withstand the forces within an aortic such that the heart valve can maintain a valvular shape and continue regenerative growth post
  • a surrounding wall has enough compressive strength to prevent collapse of a regenerative heart valve due to
  • a surrounding wall has enough fatigue strength such that a regenerative heart valve is able to withstand pulsatile pressures associated with systole and diastole.
  • pressures within aortic root can be approximately 120 systolic mmHg in a typical human, and can reach above 150 systolic mmHg or even 180 systolic mmHg in an individual suffering from severe hypertension.
  • a regenerative heart valve is able to withstand pressures of at least 100 mmHg, 110 mmHg, 120 mmHg, 130 mmHg, 140 mmHg, 150 mmHg, 160 mmHg, 170 mmHg, or 180 mmHg.
  • a surrounding wall is biodegradable.
  • a number of synthetic biodegradable polymers can be used, in accordance with various embodiments, to construct a surrounding wall, including (but not limited to) polyglycolic acid (PGA), polylactic acid (PLA), poly-Ddactide (PDLA), polyurethane (PU), poly-4-hydroxybutyrate (P4HB), and polycaprolactone (PCL). It should be understood that multiple materials can be combined to construct a surrounding wall.
  • a surrounding wall is degraded after implantation over a period of time, which may allow host cells to migrate into and proximate to the wall such that the host cells can strengthen a native aortic root wall after the implanted wall is degraded.
  • the surrounding wall will no longer be needed when the regenerative valve converts into host living tissue and adapts to the local environment, including withstanding forces within the aortic root.
  • a biodegradable surrounding wall will degrade in a timeframe of 6 to 36 months. In some specific embodiments, a biodegradable surrounding wall will degrade in approximate 6, 12, 18, 24, 30 or 36 months. It should be understood that the material selected and thickness of a biodegradable surrounding wall can be selected such that the time frame to degrade can be manipulated.
  • a number of embodiments are direct to engineering the internal face of a surrounding wall to promote regeneration of a regenerative heart valve and native aortic root.
  • a surrounding wall is contoured with a micropattern on the internal face such that it promotes formation of an endotheliumdike tissue layer.
  • a surrounding wall is coated and/or impregnated on the internal face with bioactive molecules to promote regeneration.
  • micropatterning and/or use of bioactive molecules prevent improper pannus formation, which can result in destructive scar tissue at the site of implantation.
  • the internal face of a surrounding wall is contoured with a set of furrows and/or ridges to promote endothelialization and mitigate pannus formation.
  • Methods to micropattern a surface are known in the art, such as methods described in the U.S. Patent Application Publication No. 2015/0100118 of J. A. Benton entitled“Method for Directing Cellular Migration Patterns on a
  • Bio Tissue the disclosure of which is herein incorporated by reference. It is noted that polymeric surfaces, such as the internal face of a surrounding wall, can be micropatterned in a similar manner to biological tissue.
  • micropattern includes a set of furrows and/or ridges on a surface that both dimension and offset at a distance that is greater than the average size of a fibroblast or other cell associated with pannus formation.
  • Fibroblasts are believed to have a size in the range of 20 to 40 microns and more typically from 10 to 20 microns.
  • adjacent parallel furrows are offset at a distance of at least 10 microns, at least 20 microns, at least 30 microns or at least 40 microns.
  • each individual furrow has width and/or depth of at least 10 microns, at least 20 microns, at least 30 microns or at least 40 microns.
  • parallel furrows are curved.
  • a grid pattern of intersecting parallel furrows are employed.
  • the internal face of a surrounding wall is coated and/or impregnated with bioactive molecules to promote regeneration and
  • VEGF vascular endothelial growth factor
  • bFGF basic fibroblast growth factor
  • TGF-h transforming growth factor-b
  • ANGPT1 angiopoietin 1
  • ANGPT2 angiopoietin 2
  • IGF-1- a insulindike growth factor 1
  • SDF-1- a stromal-derived factor- 1-a
  • anti-inflammatory factors to be provided include (but not limited to) curcumin and flavonoids.
  • various biological cells are integrated within or coated onto the internal face of a surrounding wall that help promote regeneration and differentiation with the native aortic root.
  • a number of cell sources can be utilized.
  • cells sources include (but are not limited to) mesenchymal stem cells (e.g ., derived from bone marrow), cardiac progenitor cells, endothelial progenitor cells, adipose tissue, vascular tissues, amniotic fluid-derived cells, and cells
  • vascular tissue is derived from peripheral arteries and/or umbilical veins, which can be used to isolate endothelial cells and myofibroblasts for regenerative tissue formulation.
  • pluripotent stem cells are induced into a pluripotent state from a mature cell (e.g., fibroblasts).
  • cells are sourced from an individual to be treated, which reduces concerns associated with allogenic sources.
  • a number of embodiments are directed to methods of delivering a
  • a method can be performed on any suitable recipient, including (but not limited to) humans, other mammals (e.g., porcine), cadavers, or anthropomorphic phantoms, as would be understood in the art. Accordingly, methods of delivery include both methods of treatment (e.g., treatment of human subjects) and methods of training and/or practice (e.g., utilizing an anthropomorphic phantom that mimics human vasculature to perform method). Methods of delivery include (but not limited to) open heart surgery and transcatheter delivery.
  • any appropriate approach may be utilized to reach the site of deployment, including (but not limited to) a transfemoral, subclavian, transapical, or transaortic approach.
  • a catheter containing a surrounding wall and/or regenerative valve is delivered via a guidewire to the site of deployment.
  • a wall and/or regenerative valve is released from the catheter and then expanded into form such that the wall is surrounding a regenerative heart valve.
  • a number of expansion mechanisms can be utilized, such as (for example) an inflatable balloon, mechanical expansion, or utilization of a self-expanding device.
  • Particular shape designs and radiopaque regions on the frame and/or on the cover can be utilized to monitor the expansion and implementation.
  • a surrounding wall and/or regenerative valve may be utilized in a variety of applications.
  • a surrounding wall and/or regenerative device is delivered to a site for valve replacement, especially replacement of an aortic valve.
  • Regenerative tissue to be utilized in a regenerative heart valve can be any appropriate formulation of regenerative tissue as understood in the art.
  • regenerative tissue is formulated in vitro.
  • regenerative tissue is autologous (e.g., generated from tissue and or cells of the individual to be treated).
  • regenerative tissue is allogenic (e.g., generated from a source other than the individual to be treated). When allogenic tissue is be used, in accordance with some embodiments, appropriate measures to mitigate immunore activity and/or rejection of the tissue may be necessary.
  • regenerative tissue is formulated such that regenerative heart valve is able to grow, adapt, and integrate within the aortic root after implantation. Growth and adaptation is especially critical for heart valve replacement in children, which may avoid the necessity of multiple valve replacement surgeries as the child grows.
  • a regenerative heart valve is formulated to resist thrombosis and pannus formation.
  • a regenerative heart valve is “trained” in bioreactor systems that simulate physiological and mechanical pressures that occur in the aortic root.
  • regenerative tissue is formulated on a scaffold such that the tissue grows into an appropriate heart valve shape.
  • scaffolds are biodegradable such that when implanted and/or a short time after implantation, the scaffold degrades leaving behind only the regenerative tissue.
  • a number of scaffold matrices can be used, as understood in the art. In some
  • a synthetic polymer such as (for example) polyglycolic acid (PGA), polylactic acid (PLA), poly-Ddactide (PDLA), polyurethane (PU), poly-4-hydroxybutyrate (P4HB), and polycaprolactone (PCL).
  • PGA polyglycolic acid
  • PLA polylactic acid
  • PDLA poly-Ddactide
  • PU polyurethane
  • P4HB poly-4-hydroxybutyrate
  • PCL polycaprolactone
  • a biological matrix is used, which can be formulated from a number of biomolecules including (but not limited to) collagen, fibrin, hyaluronic acid, alginate, and chitosan.
  • a decellularized extracellular matrix is used as a scaffold. It should be understood that various scaffold matrices can be combined and utilized in accordance with various embodiments.
  • cells sources include (but are not limited to) mesenchymal stem cells (e.g ., derived from bone marrow), cardiac progenitor cells, endothelial progenitor cells, adipose tissue, vascular tissues, amniotic fluid-derived cells, and cells
  • pluripotent stem cells including embryonic stem cells.
  • vascular tissue is derived from peripheral arteries and/or umbilical veins, which can be used to isolate endothelial cells and myofibroblasts for regenerative tissue formulation.
  • pluripotent stem cells are induced into a pluripotent state from a mature cell (e.g., fibroblasts).
  • cells are sourced from an individual to be treated, which reduces concerns associated with allogenic sources.
  • bioactive molecules including regenerative and differentiation factors are provided with regenerative tissue to stimulate host
  • extracellular growth factors, cytokines and/or ligands can be provided to stimulate regenerative growth and vascular differentiation.
  • factors that to be provided include (but are not limited to) vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF), transforming growth factor-b (TGF-b), angiopoietin 1 (ANGPT1), angiopoietin 2 (ANGPT2), insulin-like growth factor 1 (IGF-1) and stromal-derived factor- 1-a (SDF-1- a).
  • VEGF vascular endothelial growth factor
  • bFGF basic fibroblast growth factor
  • TGF-b transforming growth factor-b
  • ANGPT1 angiopoietin 1
  • ANGPT2 angiopoietin 2
  • IGF-1 insulin-like growth factor 1
  • SDF-1- a stromal-derived factor- 1-a
  • anti-inflammatory factors to be provided include (but not limited to) curcumin and flavonoids.
  • a regenerative heart valve is to be inserted into an aortic root to replace a dysfunctional aortic valve, where the forces related to systole and diastole pressures are extremely strong and repetitive.
  • regenerative heart valves are generally composed of soft tissue and are highly plastic, they lack sufficient rigidity to withstand strong pulsatile pressures.
  • a newly implanted regenerative heart valve can be forced to collapse, causing great damage and preventing the valve from properly integrating the aortic root. Further growth and regeneration within the aortic root can also be inhibited as host cells will not have the ability to migrate and assimilate within the regenerative valve. Accordingly, several embodiments are directed to providing reinforcing elements that provide structural rigidity capable of
  • reinforcing elements maintain a regenerative heart valve’s shape and functionality while under stress from the blood pressure forces.

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Abstract

L'invention concerne des dispositifs et des procédés pour renforcer une valvule cardiaque régénérative. Un élément de renforcement peut fournir une structure et une rigidité pour résister à des contraintes qui se produisent à l'intérieur de la racine aortique. Dans certains cas, un anneau de support est fixé à une valvule cardiaque régénérative. Dans certains cas, une paroi tubulaire entoure une valvule cardiaque régénérative.
PCT/US2020/015892 2019-02-04 2020-01-30 Valvules cardiaques régénératrices renforcées WO2020163150A1 (fr)

Priority Applications (4)

Application Number Priority Date Filing Date Title
EP20708898.0A EP3920848A1 (fr) 2019-02-04 2020-01-30 Valvules cardiaques régénératrices renforcées
CN202080021587.8A CN113573668A (zh) 2019-02-04 2020-01-30 强化再生心脏瓣膜
CA3127232A CA3127232A1 (fr) 2019-02-04 2020-01-30 Valvules cardiaques regeneratrices renforcees
US17/393,624 US20210361421A1 (en) 2019-02-04 2021-08-04 Reinforced regenerative heart valves

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US201962800853P 2019-02-04 2019-02-04
US62/800,853 2019-02-04

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CA3127232A1 (fr) 2020-08-13

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